Synthesis of n-substituted 2-aminoethanethiosulfuric acids

ABSTRACT

A PROCESS FOR THE SYNTHESIS OF N-SUBSTITUTED 2-AMINOETHANETHIOSULFURIC ACIDS OF THE FORMULA:   R-NH-CH2-CH2-SSO3H   WHEREIN R REPRESENTS ALKYL OR PHENYL ALKYL BY REACTING AMMONIUM THIOSULFATE WITH A 1-SUBSTITUTED AZIRIDINE. THE COMPOUNDS MADE BY THIS PROCESS ARE EFFECTIVE ANTIRADIATION AGENTS FOR ANIMALS.

United States Patent O 3,655,715 SYNTHESIS OF N-SUBSTITUTED 2-AMINO- ETHANETHIOSULFURIC ACIDS Daniel L. Klayman, Chevy Chase, Md., and W. Frankhn Gilmore, Oxford, Miss., assignors to the United States of America as represented by the Secretary of the Army No Drawing. Application June 17, 1968, Ser. No. 737,358,

now Patent No. 3,595,899, dated July 27, 1971, which is a continuation-in-part of application Ser. No. 506,291,

Nov. 3, 1965. Divided and this application July 15,

1969, Ser. No. 870,883

Int. Cl. C07c 141/00 US. Cl. 260-453 R 1 Claim ABSTRACT OF THE DISCLOSURE A process for the synthesis of N-substituted 2-arninoethanethiosulfuric acids of the formula:

wherein R represents alkyl or phenyl alkyl by reacting ammonium thiosulfate with a l-substituted aziridine. The compounds made by this process are effective antiradiation agents for animals.

The invention described herein may be manufactured and used by or for the Government for governmental purposes without the payment to us of any royalty thereon.

CROSS REFERENCE TO RELATED APPLICATIONS This is a divisional application of application Ser. No. 737,358, filed June 17, 1968 (now US. Pat. 3,595,899, issued July 27, 1971), which is a continuation-in-part application of application Ser. No. 506,291, filed Nov. 3, 1965, now abandoned.

BACKGROUND OF THE INVENTION (1) Field of the invention It has been discovered that N-substituted aminoethanethiosulfuric acids of the general formula:

wherein R represents an alkyl, preferably having from 1 to 18 carbon atoms, or a phenyl alkyl wherein the alkyl chain has from 1 to '6 carbon atoms, are effective antiradiation drugs for mammals.

(2) Description of the prior art Destruction of cellular components from radiation exposure has been thought to result either because the radioactive particles cause the direct inactivation of some essential component of the cell by ionization, or'indirect inactivation by an' intermediate which is produced by radiation and which then reacts with a critical component. See Thomson, Radiation Protection in Mammals, 5, Reinhold Publishing Co. (1962).

It has been found that certain chemicals, introduced into the body prior to exposure, act as protective agents thereby permitting the body to sustain an amount of radiation which would constitute a lethal dosage without the introduction of said chemical compounds.

Laboratory experiments use as a criterion a 30 day ice LD This term is defined as that amount of radiation required to cause the death of all of the exposed subjects within 30 days. For example, to cause the death of 50 percent in 30 days the LD for mice varies from 400 to 700 roentgens (hereinafter referred to as r.) depending on the strain. The LD for some strains of guinea pigs is about 200 r. and around 800 r. for rabbits. The 30 day LD for man is estimated at between 400 and 500 r. Exact data depends on many variables such as age, sex, and diet. See Thomson, p. 10. Other meaningful criteria involve a correlation between the dose rate in milligrams per kilogram of body weight and percent survival.

Laboratory procedure in evaluating a chemical as a radiation protective agent usually follows the procedure of injecting a sublethal dose of the chemical dissolved in water into groups of subjects, and then evaluating the new LD for the exposed animals. The activity of a chemical protective agent is evaluated on the basis of the increased LD after injection with the agent, against a control group. For example, Smith et al. in 73 Proc. Sec. Exptl. Biol. Med. 198 (1950) disclosed that 1000 r. given an animal previously treated with 1200 mg./kg. of cysteine will produce the same degree of mortality as 600 r. in an untreated animal (cited in Thomson, p. 5 6) It is known that 'various thiols are effective antiradiation compounds. See Thomson, p. 53. Rosenthal in US. Pat. No. 3.284,297, issued Nov. *8, 1966, disclosed that 2- N-methylammoniumethylthiosulfuric acid was an effective antiradiation compound. However, research in the area of thiosulfuric acids was abandoned due to the fact that an enormous dosage of around 300 mg./kg. was necessary with the lower alkyl substituent in order to achieve only a percent survival ratio.

SUMMARY OF THE INVENTION It has now been discovered that certain higher alkyl and phenyl alkyl N-substituted Z-aminoethanethiosulfuric acids are particularly eifective antiradiation drugs having a high LD, and a high efficiency for a relatively small dosage. These new compounds are also synthesized according to three new processses hereinafter described.

Accordingly, it is an object of this invention to synthesize the N-substituted family of Z-aminoethanethiosulfuric acids.

It is another object to provide N substituted 2- aiminoethanethiosulfuric acids for use as antiradiation rugs.

It is a further object to provide N-substituted 2-aminoethanethiosulfuric acids having low toxicity for mammals, and highly efficient antiradiation properties in mammals.

These and other objects will be obvious with reference to the following description.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following table lists fifty-one compounds synthesized according to the processes of the invention and compiles the results of tests according to standard laboratory procedures on test groups of rodents. The table compares radiation dosage with drug dosage per kilogram of body weight to achieve percent survival or efliciency. The table also contains toxicity data in terms of an LD evaluated over 1 or 2 days. The period of time is short because the rodents normally die within one day. The data was complied using ordinary laboratory procedures.

Rodent Time drug dose Radiation interval Percent LD Compound Formula (mg/kg.) dose (r) (min.) Survival (mg./kg.)

CaHoNOsS: 300 800 15 70 350 CAHHNOBSZ 300 1, 000 30 55 525 C5H13N 532 225 925 15 30 350 C 0H15N 0 a 200 1, 000 15 7 300 C7H17NO S2 50 1,000 30 0 200 CBHNNOESZ 75 1,000 15 0 85 n 21NOa 2 75 1,000 30 50 125 10H2sN 3 2 15 1, 000 30 80 125 11H25N S2 15 1, 000 30 87 40 C12H27N03S2 5 975 30 90 13 isfiznN asz 5 1, 000 15 0 8 C14HMN03S2 5 1, 000 30 0 CIEHBQNOQSZ 5 1,000 30 40 15 01515551103 5 5 1,000 30 10 C17H37 0 2 1, 000 30 7 CIBHsQN o 1 40 825 30 O 150 n-Heptadeeyl- CmHnNOaSz 100 800 30 0 200 n-OctadecyL- CzaHnNO as: 250 800 30 0 400 C5H13NO3S2 250 800 30 0 270 CoHiaNO 352 150 1, 000 15 0 300 CBHIBNO as: 200 825 15 10 250 C7H17NO7S2 200 1, 000 15 0 475 Oyclobutyhnethy C1H15N0 5 2 100 1, 000 15 0 180 2- e o ziNoa z 75 1, 000 15 0 175 0 10N03Sz 1,000 15 0 CHI ZaN 352 75 1, 000 30 138 oio zs ssa 75 1, 000 30 40 125 cio zaNoasz 75 800 15 33 140 CioHnNOzBa 100 800 15 33 150 roHraNOaS-a 1, 000 15 53 180 CnHisNOaSa 40 1, 000 15 47 140 CuHnNO 532 22. 5 825 30 94 50 C11 25NO3S2 50 825 15 80 C11H25NO3S2 75 800 15 20 200 11 25 aS2 20 1,000 30 13 100 CxzHwNOzSz 15 1, 000 30 94 25 37 3-decy 12 21N 11 1 25 800 15 80 100 38 3,7-dimethyloctyl C1zH27N0aSz 30 1, 000 30 87 125 39- Z-undec l3 27 3 2 10 s25 30 5a 20 4o- Cycloundecylmethyl. CM WN s H 38 1,000 30 7 150 41 C9H13N03S2 150 1, 000 30 0 250 42- 4-methyloxyb enzyl- C 10H15N04S2 100 1, 000 15 0 180 43- Phone hyl C10H15NO3S2 50 800 15 0 150 44. 3-phenylpropyl uHnN 332 50 1, 000 15 40 125 45- 2-phenylbutyL. Cu w Oa a 50 1, 000 30 13 125 46- 4-phenylbuty1 olz ivNoasa 120 825 30 94 300 47 5-pheny1penty1. cia ziNoa a 70 825 15 83 48 fi-phenylhex u za a z 25 1, 000 30 27 38 49 9-acrldyl 15 14 2 a a 25 225 30 o 50 50.. 3- (n-methoxy) -phenylpropyl C12 nNO4 7 50 825 15 7 51 3,3,3Ftripheny1propy1 2a 25 3 2 5 1, 000 30 0 140 The following example illustrates this invention.

EXAMPLE I Preparation of methylaminoethanethiosulfuric acid l-methylaziridine (5.71 g., 0.10 mole) was added to a stirred mixture of 18.53 g. (0.125 mole) of ammonium thiosulfate and 250 m1. of methanol. The entire mixture was heated for 4 hours during which time ammonia was evolved. The excess ammonium thiosulfate was removed by filtration and the filtrate was evaporated to dryness. The residue was recrystallized from water-ethanol to give 8.8 g. (51.4 percent) of methylaminoethanethiosulfuric acid, melting point C. The infrared spectrum was identical to that obtained from the product made by another method.

Analysis.-Calcd. for C H NO S (percent): S, 37.45. Found (percent): S, 37.51.

This procedure may be applied to the preparation of the N -substituted acid from l-substituted aziridine having a substituted alkyl group with from 1 to 13 carbon atoms or a phenyl alkyl group wherein the alkyl chain has from 1 to 6 carbon atoms.

We claim:

1. A process for the synthesis of N-substituted aminoethanethiosulfuric acid of the formula:

wherein R is a member selected from the group consisting of linear alkyl having 1 to 4, 7 to 10, and 13 carbon atoms, branched alkyl having from 8 to 11 carbon atoms, and phenyl alkyl wherein the alkyl chain has from 1 to 6 carbon atoms comprising:

(a) reacting at reflux temperature in methanol solution a molar excess of ammonium thiosulfate with a 1- substituted aziridine of the general formula:

References Cited Schaefer et a1. Monoand Bis-(l-Aziridinyl)-s-Triazines, 1955 JACS, pp. 5918-22.

Citarel et al., Prep. of Radioactive Protective Agents, (1963) pp. 1 and 5. US. Govt. Tech. Report #AD294344 Astia 1963.

Klayman et al. The Opening of Aziridines with Ammonium Thiosulfate (1965) (Chem. & IND. 38 p. 1632 September 1965.

Rosenthal et al., The Synthesis of 5 Amino Mercaptans etc., (1965) J. Org. Chem. 30, pp. 3689 and 3694 (1965).

ELBERT L. ROBERTS, Primary Examiner G. 'HOLLRAH, Assistant Examiner 

